rs587776441
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The ENST00000387342.1(MT-TV):n.43G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Mitomap GenBank:
Absent
Consequence
MT-TV
ENST00000387342.1 non_coding_transcript_exon
ENST00000387342.1 non_coding_transcript_exon
Scores
Mitotip
Uncertain
Clinical Significance
Leigh-Syndrome-/-HCM-/-MELAS,Adult-Leigh-Syndrome
Conservation
PhyloP100: 0.980
Genes affected
MT-TV (HGNC:7500): (mitochondrially encoded tRNA valine)
MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]
MT-RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
?
No frequency data in Mitomap. Probably very rare.
PP5
?
Variant M-1644-G-A is Pathogenic according to our data. Variant chrM-1644-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 689846.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRNV | TRNV.1 use as main transcript | n.43G>A | non_coding_transcript_exon_variant | 1/1 | |||
RNR2 | RNR2.1 use as main transcript | upstream_gene_variant | |||||
RNR1 | RNR1.1 use as main transcript | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-TV | ENST00000387342.1 | n.43G>A | non_coding_transcript_exon_variant | 1/1 | |||||
MT-RNR2 | ENST00000387347.2 | upstream_gene_variant | |||||||
MT-RNR1 | ENST00000389680.2 | downstream_gene_variant |
Frequencies
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Gnomad homoplasmic
AF:
AC:
0
AN:
56431
Gnomad heteroplasmic
AF:
AC:
1
AN:
56431
Mitomap
Leigh-Syndrome-/-HCM-/-MELAS,Adult-Leigh-Syndrome
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Jul 12, 2019 | The NC_012920.1:m.1644G>A variant in MT-TV gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PS5, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Mitochondrial disease Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Dec 10, 2021 | The m.1644G>A variant in MT-TV was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in 7 individuals with primary mitochondrial disease with variable features including cardiac (hypertrophic cardiomyopathy, LBBB); neurologic (neurodegeneration/dementia, stroke-like episodes, recurrent encephalopathy, epilepsy, ataxia, dystonia, Parkinsonism, mood disorder/disturbances, fatigue, muscle weakness, exercise intolerance, neuropathy, cognitive impairment, developmental regression); audiologic (bilateral sensorineural hearing loss); renal (cystic renal disease); GI (severe GI dysmotility, cachexia); and endocrine (diabetes) concerns as well as lab abnormalities (elevated blood and CSF lactate, elevated CK), and brain imaging abnormalities (atrophy, basal ganglia lesions, MRS lactate peak); with heteroplasmy levels in multiple tissues ranging from 85% to homoplasmy (PS4; PMIDs: 15320572, 23847141, 18314141, 21986556, 24691472). This variant heteroplasmy level segregated with severity in 2 family members from 1 family (PP1; PMID: 15320572). This variant is located at the same position as another variant associated with mitochondrial disease, m.1644G>T (PM5_supporting). This variant is absent in the GenBank data set and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA, as does HmtVar with a score of 1 (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 24691472). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PS3_supporting, PM2_supporting, PM5_supporting, PP1, PP3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Mitotip
Uncertain
Hmtvar
Pathogenic
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at